Ladakis Dimitrios C, Harrison Kimystian L, Smith Matthew D, Solem Krista, Gadani Sachin, Jank Larissa, Hwang Soonmyung, Farhadi Farzaneh, Dewey Blake E, Fitzgerald Kathryn C, Sotirchos Elias S, Saidha Shiv, Calabresi Peter A, Bhargava Pavan
Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, United States.
medRxiv. 2024 Jan 23:2024.01.17.24301393. doi: 10.1101/2024.01.17.24301393.
Bile acid metabolism is altered in multiple sclerosis (MS) and tauroursodeoxycholic acid (TUDCA) supplementation ameliorated disease in mouse models of MS.
Global metabolomics was performed in an observational cohort of people with MS followed by pathway analysis to examine relationships between baseline metabolite levels and subsequent brain and retinal atrophy. A double-blind, placebo-controlled trial, was completed in people with progressive MS (PMS), randomized to receive either TUDCA (2g daily) or placebo for 16 weeks. Participants were followed with serial clinical and laboratory assessments. Primary outcomes were safety and tolerability of TUDCA, and exploratory outcomes included changes in clinical, laboratory and gut microbiome parameters.
In the observational cohort, higher primary bile acid levels at baseline predicted slower whole brain, brain substructure and specific retinal layer atrophy. In the clinical trial, 47 participants were included in our analyses (21 in placebo arm, 26 in TUDCA arm). Adverse events did not significantly differ between arms (p=0.77). The TUDCA arm demonstrated increased serum levels of multiple bile acids. No significant differences were noted in clinical or fluid biomarker outcomes. Central memory CD4+ and Th1/17 cells decreased, while CD4+ naïve cells increased in the TUDCA arm compared to placebo. Changes in the composition and function of gut microbiota were also noted in the TUDCA arm compared to placebo.
Bile acid metabolism in MS is linked with brain and retinal atrophy. TUDCA supplementation in PMS is safe, tolerable and has measurable biological effects that warrant further evaluation in larger trials with a longer treatment duration.
多发性硬化症（MS）患者的胆汁酸代谢发生改变，补充牛磺熊去氧胆酸（TUDCA）可改善MS小鼠模型中的疾病状况。
对一组MS患者进行了全代谢组学研究，随后进行通路分析，以检查基线代谢物水平与随后的脑和视网膜萎缩之间的关系。在进行性MS（PMS）患者中完成了一项双盲、安慰剂对照试验，随机分配患者接受TUDCA（每日2克）或安慰剂治疗16周。对参与者进行了系列临床和实验室评估。主要结局是TUDCA的安全性和耐受性，探索性结局包括临床、实验室和肠道微生物组参数的变化。
在观察队列中，基线时较高的初级胆汁酸水平预示着全脑、脑亚结构和特定视网膜层萎缩速度较慢。在临床试验中，我们的分析纳入了47名参与者（安慰剂组21名，TUDCA组26名）。两组之间的不良事件无显著差异（p = 0.77）。TUDCA组的多种胆汁酸血清水平升高。在临床或体液生物标志物结局方面未观察到显著差异。与安慰剂组相比，TUDCA组的中枢记忆CD4 +和Th1/17细胞减少，而CD4 +幼稚细胞增加。与安慰剂组相比，TUDCA组的肠道微生物群的组成和功能也发生了变化。
MS中的胆汁酸代谢与脑和视网膜萎缩有关。PMS患者补充TUDCA是安全、可耐受的，并且具有可测量的生物学效应，值得在更长治疗时间的更大规模试验中进一步评估。
